This invention relates to polymorphic markers indicative of the propensity for longevity and methods for using such markers, and more particularly to genetic loci on a specified region of human chromosome 4 associated with exceptional longevity.
It has long been suspected that a genetic predisposition exists for longevity in humans. For example, many studies have documented the inheritance of human longevity. McGue et al., J. Gerontol. Biol. Sci., 48: B237-44 (1993); Ljungquist et al., J. Gerontol. Biol Sci., 53: M441-46 (1998). Studies have also documented that centenarians (individuals who live for 100 years or more) are more likely than non-centenarians to have siblings who are long-lived. In particular, one study has shown that the siblings of centenarians have an approximately four-fold greater probability of survival to age 91 than siblings of non-centenarians. Perls et al., Lancet, 351: 560 (1998). A more recent study has shown that female siblings of centenarians have over an eight-fold greater probability of survival to age 100 than siblings of non-centenarians and male siblings of centenarians have over an eleven-fold greater probability of survival to age 97 than siblings of non-centenarians.
Individuals who achieve exceptional longevity, such as centenarians, tend to live the majority of their lives in excellent health, demonstrating a rapid decline only at the end of their lives. Hitt et al., Lancet, 354: 652 (1999). A relative lack of polymorphic variants associated with diseases of aging may be one prerequisite to achieving exceptional longevity. For example, the absence of genetic polymorphisms among centenarians is exemplified by the rarity of the apolipoprotein E xcex5-4 allele that has been associated with Alzheimer""s disease and cardiovascular disease. Schxc3xa4chter et al., Nat. Genet., 6: 29-32 (1994); Rebeck et al., Neurology, 44: 1513-16 (1994). Another prerequisite to achieving exceptional longevity may be the ability to modulate the rate of the aging process, which also appears to have a genetic component. For example, one study has shown that the offspring of centenarians had more favorable lipid profile characteristics compared to ethnically matched and unmatched controls. Barzilai et al., J. Am. Geriatr. Soc., 49: 76-79 (2001). These and other observations indicate that there may be one or more genetic loci that influence longevity.
Genetic studies in other species including mammals indicate that specific genetic polymorphisms have powerful influences upon life span (defined by the age of the oldest member of the species). A number of studies on non-human species indicate that a relatively few genetic polymorphisms have a powerful influence upon the ability to achieve exceptional longevity. Many of those polymorphisms appear to play roles in basic mechanisms of metabolism and aging.
Only recently have researchers begun to investigate a genetic link to exceptional longevity. One approach to determining the significance of genes having an influence on longevity is to screen for polymorphisms in human homologs and to determine the allelic frequencies among specific human phenotypes, such as centenarians, and compare them to ethnically matched younger controls. Alternatively, case-control studies can be performed on a priori-selected candidate genes chosen because of their hypothesized roles in fundamental mechanisms of aging. These basic mechanisms might include modulation of genomic instability, for example by DNA repair and anti-oxidant defenses, gene expression, cell proliferation and senescence, maintenance of differential function, and signal transduction. The drawbacks of such studies include the improbability of picking the right gene to study out of the myriad known and unknown genes effecting the process of interest.
Knowledge of longevity-associated polymorphisms would not only provide the benefit of predicting individual longevity, but would also provide the ability to predict the likelihood of age-associated diseases. Making such predictions would allow early prophylaxis that would reduce the severity of or would eliminate the occurrence of such diseases. Accordingly, there is a need in the art for genetic loci associated with longevity and methods of using polymorphic markers indicative of the propensity for longevity. Such genetic loci and methods are provided herein.
This invention provides a genetic locus associated with extreme longevity. According to the invention, a specified region of human chromosome 4 is linked to the propensity for old age. In particular, the invention provides a longevity locus with a linkage at the D4S1564 marker (also referred to as AFM248zg9, 248zg9, and Z23817) on human chromosome 4. According to the invention, the presence of a familial linkage to the D4S1564 marker on human chromosome 4 is indicative of a polymorphic variant associated with increased likelihood for longevity. Detection of an inherited variant at the D4S1564 marker, or a polymorphism within the longevity locus containing the D4S1564 marker, is indicative of the propensity for extreme old age.
In a preferred embodiment, the invention provides a polymorphic marker contained in an approximately 10-20 cM region surrounding the D4S1564 marker. In a further embodiment, the invention provides a marker within 20 cM of position 112.6 on human chromosome 4. Also in a preferred embodiment, the invention comprises methods for detecting a longevity marker in a biological sample. Preferably, such methods comprise amplifying DNA in the region of human chromosome 4 comprising the D4S1564 marker. The amplification product comprises a region of human chromosome 4 that contains the locus associated with longevity. The common presence of a variant of the D4S1564 marker among related individuals, at least one of whom has lived to old age, is evidence of the presence of a polymorphic variant associated with the propensity for old age.
Inherited variants of the D4S1564 marker in association with extreme longevity is indicative of the propensity for old age and the likelihood of avoiding disease of old age. For example, the invention provides the ability to predict the propensity for diseases such as heart disease, cardiovascular disease, stroke, Alzheimer""s disease, cancer, ocular disease, and numerous others associated with the aging process. Accordingly, methods of the invention are useful not only to predict the likelihood of longevity, but are also useful to indicate possible early therapeutic intervention to prevent or to lessen the effects of diseases associated with aging. Further details of the use of the invention are provided below in the detailed description thereof.